Einfluss des „Hepatocyte Growth Factor“ (HGF) auf die Sekretion der Matrix -Metalloproteinasen (MMP) 1- und 3 sowie der Tissue Inhibitors of Metalloproteinases (TIMP) 1- und 2 bei Kniegelenkssynovialfibroblasten bei der Osteoarthrose

Die Synovialfibroblasten sind neben den Chondrozyten und den Makrophagen/Monozyten zusammen mit den MMPs und den TIMPs bekanntermaßen an der Pathogenese der Osteoarthrose beteiligt. HGF ist als morphogenetischer Wachstumsfaktor bekannt und spielt bei vielen degradierenden Prozessen eine Rolle. Der Einfluss von HGF auf die MMPs und TIMPs im Rahmen der Osteoarthrose wurde bislang noch nicht überprüft. Ziel: Das Ziel der vorliegenden Arbeit war die Untersuchung des Einflusses des HGF auf die Expression von MMPs und TIMPs durch Gewebs- und Flüssigkeitssynovialfibroblasten bei osteoarthrotischem humanem Kniegelenksknorpel. Methode: Die Synovialflüssigkeit und Kniegelenkskondylenknorpel von 41 Osteoarthrosepatienten wurden gewonnen und Synovialfibroblasten und Chondrozyten kultiviert, expandiert und stimuliert. Mittels Enzyme Linked Immuno Sorbent Assay (ELISA) sollte die HGF-Konzentration in Synovialflüssigkeit in Bezug zum Osteoarthrosegrad gezeigt werden. Mit der Polymerasekettenreaktion (PCR) sollte die Transkription von HGF und seines Rezeptors c-Met in Synovialfibroblasten nachgewiesen werden. Die Einengung der MMPs auf die durch HGF relevant regulierten erfolgte durch die PCR. Die Proteasenaktivität der relevanten proMMPs -1 und -3 wurde anhand der Zymographie überprüft. Der quantitative Einfluss von HGF auf die Sekretion der MMPs -1 und -3 und der TIMPs -1 und -2 durch Gewebs- und Flüssigkeitssynovialfibroblasten wurde mittels ELISA untersucht. Ergebnisse: Der HGF-ELISA zeigte mit steigendem Osteoarthrosegrad ansteigende HGF-Konzentrationen in der Synovialflüssigkeit. HGF spielt also bei der Osteoarthrose des Kniegelenks eine Rolle. Die HGF- und c-Met-Transkription in Synovialfibroblasten wurde nachgewiesen, Synovialfibroblasten sind also Bildungs- und Wirkungsort von HGF. Die MMPs -1 und -3 werden durch HGF konzentrationsabhängig reguliert und werden im Gegensatz zu MMP-8 und -13, die nicht reguliert werden, weiter verfolgt. Pro-MMP -1 und -3 werden vor allem bei Flüssigkeitssynovialfibroblasten als proteolytisch aktiv nachgewiesen. In der quantitativen Analyse der Sekretion von MMP-1 und -3 durch Synovialfibroblasten nach HGF-Stimulation ergibt sich eine statistisch signifikante, dosisabhängige Steigerung für MMP-1 und -3 (p < 0,001). TIMP-1 und -2 werden in Synovialfibroblasten durch HGF nicht konzentrationsabhängig reguliert. Schlussfolgerung: Neben den bekannten Zytokinen (z.B. IL-1β oder TNF-α) scheint HGF in die Pathogenese der Osteoarthrose durch Induzierung der bekanntermaßen im Arthroseprozess beteiligten MMPs -1 und -3 involviert zu sein. Die Arbeit unterstreicht die Rolle der Synovialfibroblasten bei der Pathogenese der Osteoarthrose

Aggressivität, Assertivität und sexuelle Devianz : eine empirisch-quantitative Prüfung der Stoller’schen Perversionstheorie

Es wird eine Studie präsentiert, in der die psychodynamisch begründete Perversionstheorie von Robert D. Stoller (1979) empirisch überprüft wird. Nach Stoller können nach (früheren) traumatischen Erfahrungen aggressive Impulse in sexuell deviante Fantasien transformiert werden. Geprüft werden einzelne Aspekte dieser Theorie anhand einer umfangreichen Stichprobe von N = 954 Personen, die aufgrund sexuell motivierter Straftaten verurteilt und zwischen 2002 und 2018 an der Begutachtungs- und Evaluationsstelle für Gewalt- und Sexualstraftäter (BEST) im österreichischen Strafvollzug zu Vollzugszwecken ausführlich begutachtet worden sind. Dabei wurden u. a. der Fragebogen zur Erfassung von Aggressivitätsfaktoren (FAF) sowie der Grazer Assertivitätstest (GAT) verwendet. Die Ergebnisse zeigen, dass als paraphil diagnostizierte Probanden signifikant weniger spontane Aggression und weniger soziale Kompetenz als die Vergleichsgruppe ohne Paraphiliediagnose berichten. Die Ergebnisse lassen sich insofern mit der zentralen Annahme der Stoller’schen Perversionstheorie in Einklang bringen, als dass zwischen einer Paraphilie-Diagnose und selbstberichteter Aggression eine inverse Beziehung festgestellt wird

Comparison of circulating tumor cells and AR-V7 as clinical biomarker in metastatic castration-resistant prostate cancer patients

Abstract Biomarker in metastatic castration resistant prostate cancer (mCRPC) treatment are rare. We aimed to compare the clinical value of circulating tumor cells (CTCs) and androgen receptor splice variant 7 (AR-V7) as biomarker in mCRPC patients undergoing androgen receptor-targeted agent (ARTA) treatment. Overall cohort (65 patients) was stratified regarding either CTC or AR-V7 status followed by further sub-stratification of the respective other marker. Subsequently, prostate specific antigen (PSA) response, progression free survival (PFS) and overall survival (OS)) of subgroups was compared. CTCs and AR-V7 were detected in 54 (83%) and 33 (61%) patients, respectively. All AR-V7 + were CTC +. We detected PSA response in all subgroups. For PFS and OS, biomarker stratification revealed differences between all subgroups. Interestingly, no significant differences of AR-V7 transcript copy numbers were detected between responding and non-responding patients. Additionally, multivariable analysis revealed no independent prognostic value of AR-V7 positivity. Both biomarkers show clinical value in prognosticating clinical outcome. Nonetheless, AR-V7 stratification underestimates the heterogenous subgroup of CTC − and CTC + patient, the latter requiring more intense clinical surveillance. Additionally, AR-V7 level does not correlate with clinical response. Thus, the value of AR-V7 as a clinical biomarker must be considered skeptically

Does the Identification of a Minimum Number of Cases Correlate With Better Adherence to International Guidelines Regarding the Treatment of Penile Cancer? Survey Results of the European PROspective Penile Cancer Study (E-PROPS)

Background: Penile cancer represents a rare malignant disease, whereby a small caseload is associated with the risk of inadequate treatment expertise. Thus, we hypothesized that strict guideline adherence might be considered a potential surrogate for treatment quality. This study investigated the influence of the annual hospital caseload on guideline adherence regarding treatment recommendations for penile cancer. Methods: In a 2018 survey study, 681 urologists from 45 hospitals in four European countries were queried about six hypothetical case scenarios (CS): local treatment of the primary tumor pTis (CS1) and pT1b (CS2); lymph node surgery inguinal (CS3) and pelvic (CS4); and chemotherapy neoadjuvant (CS5) and adjuvant (CS6). Only the responses from 206 head and senior physicians, as decision makers, were evaluated. The answers were assessed based on the applicable European Association of Urology (EAU) guidelines regarding their correctness. The real hospital caseload was analyzed based on multivariate logistic regression models regarding its effect on guideline adherence. Results: The median annual hospital caseload was 6 (interquartile range (IQR) 3–9). Recommendations for CS1–6 were correct in 79%, 66%, 39%, 27%, 28%, and 28%, respectively. The probability of a guideline-adherent recommendation increased with each patient treated per year in a clinic for CS1, CS2, CS3, and CS6 by 16%, 7.8%, 7.2%, and 9.5%, respectively (each p < 0.05); CS4 and CS5 were not influenced by caseload. A caseload threshold with a higher guideline adherence for all endpoints could not be perceived. The type of hospital care (academic vs. non-academic) did not affect guideline adherence in any scenario. Conclusions: Guideline adherence for most treatment recommendations increases with growing annual penile cancer caseload. Thus, the results of our study call for a stronger centralization of diagnosis and treatment strategies regarding penile cancer

Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE):a randomised, open-label, multicentre, phase 3 trial

Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury). Interpretation: This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. Funding: AstraZeneca

Efficacy and Safety of Darolutamide in Patients with Nonmetastatic Castration-resistant Prostate Cancer Stratified by Prostate-specific Antigen Doubling Time : Planned Subgroup Analysis of the Phase 3 ARAMIS Trial

Background: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) have a high risk of progression to metastatic disease, particularly if their prostate-specific antigen doubling time (PSADT) is ≤6 mo. However, patients remain at a high risk with a PSADT of >6 mo. Objective: To evaluate the efficacy and safety of darolutamide versus placebo in patients stratified by PSADT >6 or ≤6 mo. Design, setting, and participants: A planned subgroup analysis of a global multicenter, double-blind, randomized, phase 3 trial in men with nmCRPC and PSADT ≤10 mo was conducted. Intervention: Patients were randomized 2:1 to oral darolutamide 600 mg twice daily or placebo, while continuing androgen-deprivation therapy. Outcome measurements and statistical analysis: The primary endpoint was metastasis-free survival (MFS). Secondary endpoints were overall survival (OS) and times to pain progression, first cytotoxic chemotherapy, and symptomatic skeletal events. Quality of life (QoL) was measured using validated prostate-relevant tools. Safety was recorded throughout the study. Results and limitations: Of 1509 patients enrolled, 469 had PSADT >6 mo (darolutamide n = 286; placebo n = 183) and 1040 had PSADT ≤6 mo (darolutamide n = 669; placebo n = 371). Baseline characteristics were balanced between subgroups. Darolutamide significantly prolonged MFS versus placebo in both subgroups (unstratified hazard ratio [95% confidence interval]: PSADT >6 mo, 0.38 [0.26–0.55]; PSADT ≤6 mo, 0.41 [0.33–0.52]). OS and other efficacy and QoL endpoints favored darolutamide with significant improvement over placebo in both subgroups. The incidence of adverse events, including events commonly associated with androgen receptor inhibitors (fractures, falls, hypertension, and mental impairment), and discontinuations due to adverse events were low and similar to placebo. Limitations include small subgroup populations. Conclusions: In patients with nmCRPC and PSADT >6 mo (maximum 10 mo), darolutamide provided a favorable benefit/risk ratio, characterized by significant improvements in MFS, OS, and other clinically relevant endpoints; maintenance of QoL; and favorable tolerability. Patient summary: In patients with prostate cancer that has stopped responding to standard hormonal therapy (indicated by an increase in prostate-specific antigen [PSA] levels), there is a risk that the cancer will spread to other parts of the body. This risk is highest when the time it takes for the PSA level to double (ie, “PSA doubling time” [PSADT]) is less than 6 mo. However, there is still a risk that the cancer will spread even if the PSADT is longer than 6 mo. In a group of patients whose PSADT was more than 6 mo but no more than 10 mo, treatment with darolutamide slowed the cancer spread and allowed them to live longer than patients who received placebo (inactive drug). Darolutamide treatment did not cause many side effects and helped maintain patients’ quality of life without disruptions.publishedVersionPeer reviewe

The Prognostic PDE4D7 Score in a Diagnostic Biopsy Prostate Cancer Patient Cohort with Longitudinal Biological Outcomes

Purpose. To further validate the prognostic power of the biomarker PDE4D7, we investigated the correlation of PDE4D7 scores adjusted for presurgical clinical variables with longitudinal postsurgical biological outcomes. Methods. RNA was extracted from biopsy punches of resected tumors (550 patients; RP cohort) and diagnostic needle biopsies (168 patients; DB cohort). Cox regression and survival were applied to correlate PDE4D7 scores with patient outcomes. Logistic regression was used to combine the clinical CAPRA score with PDE4D7. Results. In univariate analysis, the PDE4D7 score was significantly associated with PSA recurrence after prostatectomy in both studied patient cohorts' analysis (HR 0.53; 95% CI 0.41-0.67; p<1.0E-04 and HR 0.47; 95% CI 0.33-0.65; p<1.0E-04, respectively). After adjustment for the presurgical clinical variables preoperative PSA, PSA density, biopsy Gleason, clinical stage, percentage tumor in the biopsy (data only available for RP cohort), and percentage of positive biopsies, the HR was 0.49 (95% CI 0.38-0.64; p<1.0E-04) and 0.43 (95% CI 0.29-0.63; p<1.0E-04), respectively. The addition of the PDE4D7 to the clinical CAPRA score increased the AUC by 5% over the CAPRA score alone (0.82 versus 0.77; p=0.004). This combination model stratified 14.6% patients of the DB cohort to no risk of biochemical relapse (NPV 100%) over a follow-up period of up to 15 years. Conclusions. The PDE4D7 score provides independent risk information for pretreatment risk stratification. Combining CAPRA with PDE4D7 scores significantly improved the clinical risk stratification before surgery

Einfluss des „Hepatocyte Growth Factor“ (HGF) auf die Sekretion der Matrix -Metalloproteinasen (MMP) 1- und 3 sowie der Tissue Inhibitors of Metalloproteinases (TIMP) 1- und 2 bei Kniegelenkssynovialfibroblasten bei der Osteoarthrose

Die Synovialfibroblasten sind neben den Chondrozyten und den Makrophagen/Monozyten zusammen mit den MMPs und den TIMPs bekanntermaßen an der Pathogenese der Osteoarthrose beteiligt. HGF ist als morphogenetischer Wachstumsfaktor bekannt und spielt bei vielen degradierenden Prozessen eine Rolle. Der Einfluss von HGF auf die MMPs und TIMPs im Rahmen der Osteoarthrose wurde bislang noch nicht überprüft. Ziel: Das Ziel der vorliegenden Arbeit war die Untersuchung des Einflusses des HGF auf die Expression von MMPs und TIMPs durch Gewebs- und Flüssigkeitssynovialfibroblasten bei osteoarthrotischem humanem Kniegelenksknorpel. Methode: Die Synovialflüssigkeit und Kniegelenkskondylenknorpel von 41 Osteoarthrosepatienten wurden gewonnen und Synovialfibroblasten und Chondrozyten kultiviert, expandiert und stimuliert. Mittels Enzyme Linked Immuno Sorbent Assay (ELISA) sollte die HGF-Konzentration in Synovialflüssigkeit in Bezug zum Osteoarthrosegrad gezeigt werden. Mit der Polymerasekettenreaktion (PCR) sollte die Transkription von HGF und seines Rezeptors c-Met in Synovialfibroblasten nachgewiesen werden. Die Einengung der MMPs auf die durch HGF relevant regulierten erfolgte durch die PCR. Die Proteasenaktivität der relevanten proMMPs -1 und -3 wurde anhand der Zymographie überprüft. Der quantitative Einfluss von HGF auf die Sekretion der MMPs -1 und -3 und der TIMPs -1 und -2 durch Gewebs- und Flüssigkeitssynovialfibroblasten wurde mittels ELISA untersucht. Ergebnisse: Der HGF-ELISA zeigte mit steigendem Osteoarthrosegrad ansteigende HGF-Konzentrationen in der Synovialflüssigkeit. HGF spielt also bei der Osteoarthrose des Kniegelenks eine Rolle. Die HGF- und c-Met-Transkription in Synovialfibroblasten wurde nachgewiesen, Synovialfibroblasten sind also Bildungs- und Wirkungsort von HGF. Die MMPs -1 und -3 werden durch HGF konzentrationsabhängig reguliert und werden im Gegensatz zu MMP-8 und -13, die nicht reguliert werden, weiter verfolgt. Pro-MMP -1 und -3 werden vor allem bei Flüssigkeitssynovialfibroblasten als proteolytisch aktiv nachgewiesen. In der quantitativen Analyse der Sekretion von MMP-1 und -3 durch Synovialfibroblasten nach HGF-Stimulation ergibt sich eine statistisch signifikante, dosisabhängige Steigerung für MMP-1 und -3 (p &lt; 0,001). TIMP-1 und -2 werden in Synovialfibroblasten durch HGF nicht konzentrationsabhängig reguliert. Schlussfolgerung: Neben den bekannten Zytokinen (z.B. IL-1β oder TNF-α) scheint HGF in die Pathogenese der Osteoarthrose durch Induzierung der bekanntermaßen im Arthroseprozess beteiligten MMPs -1 und -3 involviert zu sein. Die Arbeit unterstreicht die Rolle der Synovialfibroblasten bei der Pathogenese der Osteoarthrose

Time after Synthesis and Time after Injection Do Not Affect Diagnostic Quality of [18F]F-PSMA 1007 PET

PET imaging using PSMA ligands is increasingly used for staging in prostate cancer patients in different clinical indications. Unlike [68Ga]Ga-labeled PSMA ligands, fluorinated compounds can be produced in large amounts; thus, they can be used for a higher number of patients. One concern is that in patients studied a long time after synthesis (TaS) or time after injection (TaI), the specific activity may decline; thus, the signal may be lower in these patients. In this study, we investigated a potential effect of TaS and TaI on image quality. In total, 134 consecutive patients were included in this retrospective analysis on the effect of TaS and TaI on uptake in prostate cancer lesions. All the patients underwent [18F]F-PSMA-1007 PET-CT from 99 min up to 549 min after tracer quality control. TaS and TaI were compared to the quantitative tumoral uptake parameters SUVmax and SUVpeak. In a second exploratory part of the analysis, TaS and TaI were correlated to a physiological tracer uptake in different organs. TaS and TaI did not affect the SUVmax and SUVpeak in tumor lesions in [18F]F-PSMA-1007 PET. The physiological uptake in salivary glands, lacrimal glands and the ganglia, spleen and urine was not significantly correlated to TaS or TaI; in contrast to the mean liver uptake, showing a weak, but significant correlation to TaS. The [18F]F-PSMA-1007 uptake in prostate cancer lesions is not significantly dependent on the TaS and TaI. These results are extremely reassuring when performing [18F]F-PSMA-1007 PET a considerable time after synthesis